Exclusive HCV Interview: Julio Gutierrez, MD

Posted on December 21, 2015

So my first question is what do you see as the biggest challenges associated with the hepatitis C epidemic in the U.S.?

JULIO GUTIERREZ: There are three main challenges currently associated with eradicating hepatitis C in the United States:

  1. Most patients in the US are still not receiving care for their hepatitis C infection. In order to cure HCV in these patients, they must be tested and referred for therapy.
  2. The availability of DAAs is currently limited by cost. Some payers have restrictions the use of DAAs in patients with mild liver disease. Additionally, with the high cost, some systems like Medicaid in Texas may not be able to afford treating all HCV patients at once.
  3. Now with multiple regimens commercially available, the final challenge is choosing the right regimen for the patient. Since many payers are only offering therapy as a single lifetime benefit, providers need to do their due diligence to identify which regimen will lead to the highest chance of SVR in their individual patients. I do not think that there’s currently a shortage of HCV providers, and I think we would be best served aiming our resources at problems #1 and #2.

Okay. You work in Texas, and I have heard that the issues regarding hepatitis C treatment varies greatly from region to region. So what are the biggest challenges you see in Texas as opposed to, say New York? Do you see any regional differences?

JULIO GUTIERREZ: Well, one issue with Medicaid in Texas is that it has not been expanded upon under the Obamacare Act. This has left over 750,000 Texans with compromised healthcare, and the State of Texas has not explained the benefit of not expanding Medicaid to its residents, other than to make a political point. So here, we still have a large number of completely unfunded patients.

If a patient has Medicaid in Texas, there’s a restriction in place which specifies that they cannot be treated if they have METAVIR fibrosis stage zero, one, or two. Finally, there is a provision regarding which the medication is allowed. Additionally, here in Texas, the P&T Committee has been slow to approve new agents, for example, daclatasvir.

And is there a reason for that?

JULIO GUTIERREZ: I’m not sure. You’ll have to ask them, but Medicaid might be wise to negotiate the best deal they can with each HCV drug manufacturer. If Medicaid only negotiates a price with one company, to pay, for example, $20,000 per treatment, what may happen is that for every 3 times that the preferred drug is used, prescribers may petition to use another drug once. If the non-negotiated federal price for the other drug is $60,000, then this drives up the average cost of therapy. Ideally, Medicaid should abandon their habit of making agents preferred, and just focus on the lowest price they can negotiate with each company. Or, they could treat the pharmaceutical companies like they treat doctors. For example, we get paid $19 for each Medicaid patient we see, and if we bill more, then “tough luck”.

Okay. And what do you think have been the most talked-about hepatitis C-related achievements this year?

JULIO GUTIERREZ: I think the further advancements associated with new regimens is exciting. We’re moving closer and closer to pan-genotypic regimens, where patients are going to require only one combination of drugs to treat all strains of hepatitis C. Shockingly, this combination has actually existed for some time, sofosbuvir and daclatasvir, but the FDA has not been helpful in making this regimen available.

The area of hepatitis C research that has grown the most is understanding the resistance to new DAAs, especially NS5A resistance. We now know that this is the variable that most likely effects SVR in two-drug regimens. Further understanding about resistance is evolving, but three-drug regimens with the addition of ribavirin is likely to offset the small decrease in SVR observed in patients with baseline resistance.

What hepatitis C-focused clinical studies or research has made an impression on you this year?

JULIO GUTIERREZ: The C-SWIFT study was really exciting. This study involves retreatment for ultra-short durations of patients who were previously treated with the same regimen. Some patients were treated for four weeks, and almost 40% were cured. Patients who failed were retreated with essentially the same regimen plus ribavirin for a longer duration, and a 100 percent cure rate was observed in those patients.

And then, I also think it’s exciting to see other new regimens such as the AbbVie combination of ABT-493 (an NS3/4a protease inhibitor) and ABT-530 (an NS5A inhibitor) move forward with good SVR rates also (as presented at AASLD 2015; SVR4 Rates with the NS3/4A Protease Inhibitor ABT-493 and NS5A Inhibitor ABT-530 in Non-Cirrhotic Treatment-Naïve and Treatment-Experienced Patients With HCV Genotype 2 or 3 Infections (SURVEYOR-2); http://abbvie.mediaroom.com/2015-11-16-AbbVie-Announces-High-Sustained-Virologic-Response-Rates-in-Phase-2-Studies-with-Pan-genotypic-Investigational-Regimen-in-Patients-with-Chronic-Hepatitis-C).

Okay, great. And I was also wondering, in your opinion, does the cost of the newer oral agents and HCV regimens introduce socioeconomic and ethical considerations in the treatment of HCV?

JULIO GUTIERREZ: Absolutely. I think on one hand, what we’re seeing is actually a reduction in price of hepatitis C therapy from what we previously had about five years ago. Dr. Andrea Branch looked at this exact question and had a paper published in Hepatology in which she described the cost of cure in patients treated with triple therapy and with an interferon-based triple therapy, and she found these costs to be much higher than what we’re actually paying now for DAAs (Bichoupan K, Martel-Laferriere V, Sachs D, et al. Hepatology. 2014 Oct;60(4):1187-95). So in a sense, the price to cure each individual hepatitis C patient has gone down, but now many more patients will be treated because cure rates are higher and side effects are lower.

In the United States, the price of drugs across the board is tremendous. It’s not just about hepatitis C, it’s about lots of other medical conditions. If you look at the cost of managing a chronic condition like diabetes over a patient’s lifetime, these costs will far exceed the cost of hepatitis C therapy. Novel cancer therapies are very expensive too. I don’t think we withhold medical therapy from any of these patients based on the price of the drugs when needed, and I do not think we should do this to hepatitis C patients.

So there are many issues with our public health system and the economics of medicine that need to be worked on, but I think if you look at future costs to the medical system and quality of adjusted life years with hepatitis C therapy, I think what we’ll see is there’s actually a real economic benefit associated with treating these patients now. The jury is still out regarding the debate on how government should be involved in deciding the exact cost of drug therapy, but it’s a fascinating question and definitely has implications that effect our society at large.

Right, yes. And actually, so my next few questions kind of speak to this topic a little further, what populations do you think will be affected or are most affected by the cost or the relatively high cost of the oral regimens?

JULIO GUTIERREZ: Well, it seems that patients with Medicaid are being significantly affected. Unfunded, impoverished patients are an unusual population because they’re actually able to get the therapy for free through compassionate use programs, but they then have to find a physician who is willing to treat them through these programs. I actually work with Dr. Barbara Turner through the Center for Research to Advance Community Health (ReACH) program (https://reach.uthscsa.edu), where we are identifying unfunded patients through a screening program, and then applying for free drug. So surprisingly, these patients have better access than average Medicaid patients.

Medicare, and then commercial patients have much better chances of getting the HCV therapies, but many of the “so-called Obamacare” insurance plans aren’t providing hepatitis C drugs uniformly. But I think in general, patients with more marginal insurances are going to suffer compared with patients with better-funded insurance plans.

Also, patients in lower socioeconomic classes tend to lack advocates, so an insurance company may feel more comfortable telling them “no”. On the other hand, I had a patient who was a lawyer who was denied therapy, and within 24 hours of him calling his insurance company, he had been approved.

Very interesting. And I was also wondering, what are your thoughts about targeting the newer oral HCV regimens to specific populations such as active injection users or incarcerated individuals?

JULIO GUTIERREZ: Well, I think there could be some potential strategies to treat these patients, but I’m concerned about treating active IV drug users because of the high risk of re-infection and depletion of resources. It may be the same with incarcerated individuals if they still maintain the same risk factors such as getting jailhouse tattoos. More work needs to be done in this field before we can say whether there is a benefit here, since re-infection and non-compliance may be an issue. At AASLD this year, Merck presented their SVR data in people who inject drugs (PWID) and it was very good, but long term follow-up is still lacking.

Another interesting population are patients who are actively using alcohol, because we know use of alcohol and concurrent hepatitis C infection dramatically increases the risk for liver cancer. So if you can’t stop a patient from using alcohol, could you potentially reduce the chance that they might need a transplant or therapy for liver cancer someday? Especially if they don’t have a real risk for hepatitis C reinfection, but can’t stop drinking? Do you withhold therapy from these patients? I advocate that these patients should be treated.

My next question is what are your thoughts about restricting hepatitis C therapy to patients with advanced fibrosis or severe complications and/or symptoms?

JULIO GUTIERREZ: I do not believe that we should wait to treat patients until they develop advanced fibrosis. In fact, these patients may be the ones that we should be treating cautiously. In patients with very advanced liver disease (decompensated, Child-Pugh B and C patients), treating their hepatitis C might result in a sort of stasis of their liver function. Many physicians have described something called “MELD purgatory”, where patients neither progress nor get better after hepatitis C therapy, and may then lose the opportunity to get a transplant.

Another aspect is that there have been post-marketing reports of patients with severe liver disease who decompensated further on HCV therapy, especially when using protease inhibitors. That’s another major concern of physicians.

Ideally, the timing of antiviral therapy could coincide with a liver transplant to avoid re-infection of the grafted liver. That’s a great challenge though because it requires quite a bit of planning. But in some patients, such as those with hepatocellular carcinoma and HCV who are undergoing transplant, the timing of transplant is more predictable and this may be accomplished.

And what do you see as the biggest challenges associated with the diagnosis and screening of hepatitis C?

JULIO GUTIERREZ: To me, it’s the connection to care and treatment right now, and that’s getting those patients who were diagnosed into the hands of a provider who can get them cured.

Okay. There also appears to be a tremendous stigma associated with having been diagnosed with hepatitis C. What are your thoughts about that?

JULIO GUTIERREZ: There are lots of patients who have hepatitis C who suffer, and are concerned about that. But I think what people need to understand is that hepatitis C is a highly curable virus, and the cure is durable and lifelong as long as the patient does not become re-infected by a new virus. So once patients are treated and cured, there is zero percent chance that they can infect another person. I think there may be some social stigma associated with, “oh, you have this”, but hepatitis C is curable.

Okay. And I was also wondering, I have read in The New York Times during the past year that there has been a tremendous spike in the incidence of HIV in certain areas such as Indiana and West Virginia. There may also be a rise in hepatitis C in these communities. Are you aware of this?

JULIO GUTIERREZ: Yes, I’m concerned. I haven’t seen those patients myself, but I’ve actually seen patients who have family in that area. It’s associated with the abuse of some over-the-counter prescription narcotics, which are becoming less available, leading to some patients turning to IV drugs again. There has been a dramatic rise in the incidence of hepatitis C in those patients, especially in this Appalachian Region. With acute hepatitis C, about 75 percent of these patients will probably end up chronically infected.

So it’s a tragedy because it’s avertable by using clean needles. But what these patients will tell you mostly is that they are using clean needles, but the mistake they make is that they all share the same well (ie, where they’re pulling the drugs into their needle from), and that’s how they’re transmitting hepatitis C to each other.

I also wanted to ask if you can share your opinions on the birth cohort screening of hepatitis C. Do you think that it has been effective?

JULIO GUTIERREZ: Oh yes, absolutely. Two out of three Americans infected with hepatitis C are born in the birth cohort of 1945 to 1965. It’s a very high-yield area for screening, and it’s very effective. It’s a great recommendation, but its uptake with PCPs is still low.

Sure. And I was wondering, so do you have any specific research interests?

JULIO GUTIERREZ: Yes, my main area of research is developing new hepatitis C therapies. And in particular, I have a clinical interest in resistance-associated variants (RAVs).

Okay, great. Did you have any abstracts at AASLD 2015 in San Francisco?

JULIO GUTIERREZ: Yes, I had a number of them actually: 39, 247, 1433, and 1900.

Abstract 39

SVR12 results from the Phase II, open-label IMPACT study of simeprevir (SMV) in combination with daclatasvir(DCV) and sofosbuvir (SOF) in treatment-naïve and -experienced patients with chronic HCV genotype ¼ infection and decompensated liver disease.

Eric Lawitz1, Fred Poordad1, Julio A. Gutierrez1, Thomas Kakuda2, Gaston Picchio3, Greet Beets4, Ann Vandevoorde4, Peter Van Remoortere2, Bert Jacquemyn4, Gemma Quinn4, Donghan Luo2, Sivi Ouwerkerk-Mahadevan5, Leen Vijgen4, Veerle Van Eygen4, Maria Beumont5; 1Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 2Janssen Research & Development, LLC, Titusville, NJ; 3Infectious Diseases, Janssen Research & Development, San Francisco, CA; 4Janssen Infectious Diseases BVBA, Beerse, Belgium; 5Janssen Research & Development, Beerse, Belgium.

  • Interim Analysis of ongoing IMPACT study (NCT02262728) assessed SMV+DCV+SOF in HCV genotype (GT)1/4-infected patients (pts) with decompensated liver disease.
  • 12 weeks of SMV+DCV+SOF resulted in 100% SVR12 in pts with decompensated liver disease for whom data were available in this interim analysis of IMPACT, and was generally safe and well tolerated.

Abstract 247

High Rates of SVR in Treatment-Experienced Patients with Genotype 1 HCV Infection and Cirrhosis After Treatment with Ledipasvir/Sofosbuvir and Vedroprevir with or Without Ribavirin for 8 weeks

Eric Lawitz1, Fred Poordad1, Robert H. Hyland2, Lin Liu2, Hadas S. Dvory2, Phillip S. Pang2, Diana M. Brainard2, Julio A. Gutierrez1; 1Texas Liver Institute, San Antonio, TX; 2Gilead Sciences, Inc, Foster City, CA

  • In the current study, we evaluated the safety and efficacy of 8 weeks of LDV/SOF plus the HCV NS3 protease inhibitor vedroprevir (VDV, GS-9451) ± RBV was evaluated in genotype 1 HCV-infected patients with cirrhosis.
  • Ledipasvir/sofosbuvir +VDV for 8 weeks achieved high SVR rates in genotype 1 HCV-infected treatment-experienced patients with cirrhosis irrespective of the addition of RBV. Both regimens were safe and well tolerated.

Abstract 1433

Safety, Pharmacokinetics, and Biologic Activity of ND-L02-s0201, a Novel Targeted Lipid-Nanoparticle to Deliver HSP47 siRNA for the Treatment of Patients with Advanced Liver Fibrosis: Interim Results from Clinical Phase 1b/2 Studies

Eric Lawitz2, Yasunobu Tanaka3, Fred Poordad2, Julio A. Gutierrez2, Kathy Carr4, Wenbin Ying1, Yoshiro Niitsu5, Kageshi Maruyama3; 1NDT, Oceanside, CA; 2Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX; 3Nitto Denko Corporation, Tokyo, Japan; 4RRD International, RRD International, LLC, Rockville, MD; 5Sapporo Medical University, Sapporo, Japan

  • Therapy for liver fibrosis is a major unmet medical need.
  • Phase 1a study and an ongoing Phase 1b/2 study results reported for a novel therapeutic modality that inhibits expression of the collagen-specific chaperone, heat shock protein 47 (HSP47), with stellate cell (SC)-specific drug delivery (Sato et al. 2008 Nature Biotech), with a goal of reversal of collagen deposition. NDL02s0201 is an injectable lipid nanoparticle formulation with a novel vitamin A analogue targeting agent for SC and a chemically modified small interfering ribonucleic acid (siRNA) active ingredient that inhibits HSP47.
  • ND-L02-s0201 was well tolerated in both studies with no dose limiting toxicities up to 0.8 mg/kg (single) and of 0.2 mg/kg/week (multiple doses).
  • Histologic improvement was seen in the majority of patients at the lowest dose studied.

Abstract 1900

A mass spectrometry based serum test for the detection of hepatocellular carcinoma (HCC) in high risk patients

Devalingam Mahalingam1, Julio A. Gutierrez1, W. Kenneth Washburn1, Glenn A. Halff1, Leonidas Chelis2, Stylianos Kakolyris2, Stylianos Vradelis3, Julia Grigorieva4, Carlos Oliveira4, Heinrich Roder4, Joanna Roder4; 1Cancer Therapy and Research Center, University of Texas Health Sciences Center San Antonio, San Antonio, TX; 2Department of Medical Oncology, Democritus University of Thrace, Alexandroupolis, Greece; 32nd Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece; 4Biodesix, Boulder, CO

  • A better biomarker for the early detection of HCC is clearly needed. Mass spectrometry analysis of serum samples combined with specialized deep learning techniques was used to train and validate such a test.
  • The developed test shows promise in the early detection of HCC as a screening tool in high risk patients independent of the cause of underlying liver disease.

So we were also wondering, did you attend any major meetings, hep C meetings this year?

JULIO GUTIERREZ: I attended EASL, and I attended some other international events in Mexico and South America.

And what interesting data did you see coming out of these meetings?

Well, let’s see. There was a meeting in Berlin (ie, the 15th Annual International Symposium on Viral Hepatitis and Liver Diseases) where they released the data for TURQUOISE-III, which showed 100 percent SVR in patients treated with the VIEKIRA PAK™ who had genotype 1b and cirrhosis, and essentially proving that you do not need to add ribavirin to this regimen when treating cirrhotic patients with HCV genotype 1b (http://www.prnewswire.com/news-releases/abbvie-announces-new-phase-3b-results-in-genotype-1b-chronic-hepatitis-c-patients-with-compensated-liver-cirrhosis-300103829.html).

And then I think the other thing that’s been interesting internationally is finding out that different drug regimens are available in different countries. Peru, for example, still only has telaprevir, while Mexico only has the VIEKIRA PAK™. So learning what everybody else has internationally, and what they have been able to do with these therapies, that’s also been very interesting.


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